Processes of making sesquiterpenoid tashironin, its analogs and their uses

ABSTRACT

A compound having the structure of the formula (genus of compound 1 excluding Tashironin or Debenzoyltashironin) 
                         
and methods of the same.

This application is a §371 national stage of PCT InternationalApplication No. PCT/US2005/046183, filed Dec. 20, 2005, and claims thebenefit of U.S. Provisional Application No. 60/637,927, filed Dec. 20,2004, the contents of all of which are hereby incorporated by referenceinto this application.

This invention has been made with government support under NationalInstitutes of Health grant HL25848. Accordingly, the U.S. Government hascertain rights in the invention.

Throughout this application various publications are referenced inparenthesis. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which this inventionpertains.

BACKGROUND

Neurotrophic factors, or neurotrophins, are agents that can preventneuronal death (neurotrophism) or promote axonal growth (neurotropism).To date, all widely studied neurotrophins (c.f. NGF, BDNF, GDNF, NT4/5,NT6) are naturally occurring polypeptides or proteins (Bennett, et al.,Auton. Neurosci. 2002, 95, 1; Lu, et al., J. Comp. Neurol. 2001, 436,456; Kaneko, J. Med. Chem. 1997, 40, 1863). Given their potential totreat neurodegenerative disorders, it is not surprising thatneurotrophic factors have been the focus of considerableinterdisciplinary research since the discovery of the firstneurotrophin, NGF, by Montalcini and Hamburger (Levi-Montalcini, et al.,J. Exp. Zool. 1951, 116, 321-362). Indeed, peptidyl neurotrophic factorshave been extensively evaluated in animal models for their ability totreat neurodegenerative disease. However, due to unfavorable drugdelivery and pharmacokinetic characteristics, in vivo evaluation ofthese neurotrophins requires direct microinjection into the brain(Kaneko, J. Med. Chem. 1997, 40, 1863; Kirik, et al., NatureNeuroscience 2004, 7, 105; Dawbarn, et al., Neuropathology and AppliedNeurobiology 2003, 29, 211-30; Pollack, et al., Curr. Drug Target CNSNeurol. Disord. 2002, 1, 59; Gonzalez, et al., Brain Res. 2001, 920, 65;Fournier, J. Pharm. Pharmacol. 1998, 50, 323). Clearly, drugavailability problems associated with these polypeptidic structures area serious impediment to their development in prospective human settings.

In 1995, Fukayama, Shida, and Kodama reported the isolation andstructural characterization of the neurotrophically inactivesesquiterpenoid tashironin (2) from the wood of illicium tashiroi(Fukuyama, et al., Tetrahedron Lett. 1995, 36, 583). More recently,Fukuyama and coworkers reported on the isolation and structureelucidation of 11-O-debenzoyltashironin (1), which promotes neuritegrowth at concentrations as low as 0.1 μmol. (Huang, et al., J. Nat.Prod. 2001, 64, 428).

Structure of Debenzoyltashironin 1 and Tashironin 2

SUMMARY OF THE INVENTION

The subject application provides for a compound having the structure ofthe formula

wherein, R₁ is H or Bz when no more than three of R₈, R₉, R₁₀ and R₁₁are H, or

-   R₁ is Bn, (C₁-C₄) alkyl, or CF₃;-   R₂ is H, (C₁-C₄) alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃;-   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl,    or OC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a    double bond or-   R₃ is O, bond α is a double bond and bond β is a single bond;-   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;-   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single    bond, or-   R₅ is O and bond γ is a double bond;-   R₆ is H, (C₁-C₄) alkyl, or CF₃;-   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide,    CH₂OCF₃ or OCF₃ and bond ε is a single bond, or-   R₇ is CH₂ and bond ε is a double bond;-   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH,    or OCF₃;-   R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a single    bond;-   R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy or    methane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and    R₁₆ are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ    is a single bond;-   R₁₁ together with R₁₂ and the carbons to which each is attached to    form an oxirane moiety form an ether group and bond δ is a single    bond; or-   R₁₁ and R₁₂ are absent and bond δ is a double bond.

The subject application also provides for a compound having thestructure of the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄)alkyl.

The subject application also provides for a composition comprising acompound having the structure of the formula

wherein,

-   R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃,-   R₂ is H, (C₁-C₄) alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃;-   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl,    or OC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a    double bond or-   R₃ is O, bond α is a double bond and bond β is a single bond;-   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;-   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single    bond, or-   R₅ is O and bond γ is a double bond;-   R₆ is H, (C₁-C₄) alkyl, or CF₃;-   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide,    CH₂OCF₃ or OCF₃ and bond ε is a single bond, or-   R₇ is CH₂ and bond ε is a double bond;-   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH,    or OCF₃;-   R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a single    bond;-   R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy or    methane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and    R₁₆ are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ    is a single bond;-   R₁₁ together with R₁₂ and the carbons to which each is attached to    form an oxirane moiety form an ether group and bond δ is a single    bond; or-   R₁₁ and R₁₂ are absent and bond δ is a double bond; and wherein the    composition is free of biological material of illicium tashiroi.

The subject application also provides for a composition comprising acompound having the structure of the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄) alkyl.

The subject application also provides for a compound having thestructure of formula

-   -   wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃;    -   R₁₉ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₀ is H, p-toluene sulfonyloxy, methane sulfonyloxy,        C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, and bond α is a single        bond or R₂₀ is O and bond α is a double bond;    -   R₂₁, R₂₄, and R₂₅ are each independently H, O(C₁-C₄)alkyl,        (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₂ is a halide, H, or (C₁-C₄)alkyl; and    -   R₂₃ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph.

The subject application also provides for a process of producing acompound of the formula

-   -   wherein,    -   R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃;    -   R₂ is H, (C₁-C₄)alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or        OCF₃;    -   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy, C(O)        (C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, bond α is a single bond and        bond β is a double bond, or    -   R₃ is O, bond α is a double bond and bond β is a single bond;    -   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;    -   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄)alkyl, or OCF₃, and bond γ is a        single bond, or    -   R₅ is O and bond γ is a double bond;    -   R₆ is H, (C₁-C₄)alkyl, or CF₃;    -   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH,        halide, CH₂OCF₃ or OCF₃ and bond ε is a single bond, or    -   R₇ is CH₂ and bond ε is a double bond;    -   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide,        OH, or OCF₃; and    -   R₁₁ and R₁₂ are each independently H, (C₁-C₄)alkyl, halide, OH,        or OCF₃ and bond δ is a single bond,    -   R₁₁ together with R₁₂ and the carbons to which each is attached        to form an oxirane moiety form an ether group and bond δ is a        single bond or    -   R₁₁ and R₁₂ are absent and bond δ is a double bond,        comprising subjecting a compound of the formula

-   -   wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₀, and R₁₁ are defined as        above; and    -   R₁₃ is —C(O)OH, —C(O)O(C₁-C₄)alkyl, or —C(O)S(C₁-C₄)alkyl,        to a tandem oxidative dearomatization-transannulation        Diels-Alder reaction to obtain the compound.

The subject application also provides for a process of producing acompound of the formula

-   -   wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃;    -   R₁₉ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₀ is H, p-toluene sulfonyloxy, methane sulfonyloxy,        C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, bond α is a single bond        and bond β is a double bond or    -   R₂₀ is O, bond α is a double bond and bond β is a single bond;    -   R₂₁, R₂₄, and R₂₅ are each independently H, O(C₁-C₄)alkyl,        (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₂ is a halide, H, or (C₁-C₄)alkyl; and    -   R₂₃ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph        comprising reacting a compound of the formula

with a compound of the formula

to obtain the compound.

The subject invention also provides a process of producing a compound ofthe formula

-   -   comprising        -   a) reacting the compounds of the formulae

-   -   wherein R₁ are defined as above, with Pd₂(dba)₃, ^(t)Bu₃P, and        DMF to obtain a compound of the formula

-   -   -   b) reacting the product of step a) with DMP and DCM to            obtain a compound of the formula

-   -   -   c) reacting the product of step b) with a compound of the            formula

-   -   BuLi, and THF to obtain a compound of the formula

-   -   -   d) reacting the product of step c) first with MsCl and TEA            and then with Me₂Cu(CN)Li₂ to obtain a compound of the            formula

-   -   -   e) reacting the product of step d) with TBAF and THF to            obtain a compound of the formula

-   -   -   f) and reacting the product of step e) with PIDA and Toluene            to thereby obtain the compound.

The subject invention further provides a process of producing a compoundof the formula

-   -   comprising        -   a) reacting a compound of the formula

with NaBH₄ and MeOH to produce a compound of the formula

-   -   -   b) reacting the product of step a) with TMS-Imid to produce            a compound of the formula

-   -   -   c) reacting the product of step b) with mCPBA and DCM to            produce a compound of the formula

-   -   -   d) reacting the product of step c) with H₂, Pd/C 5%, and            EtOAc to produce a compound of the formula

-   -   -   e) reacting the product of step d) with an acid in water to            thereby obtain the compound.

DETAILED DESCRIPTION OF THE INVENTION

The subject application provides for a compound having the structure ofthe formula

wherein, R₁ is H or Bz when no more than three of R₈, R₉, R₁₀ and R₁₁,are H, or

-   R₁ is Bn, (C₁-C₄) alkyl, or CF₃;-   R₂ is H, (C₁-C₄) alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃;-   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl,    or OC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a    double bond or-   R₃ is O, bond α is a double bond and bond β is a single bond;-   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;-   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single    bond, or-   R₅ is O and bond γ is a double bond;-   R₆ is H, (C₁-C₄) alkyl, or CF₃;-   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide,    CH₂OCF₃ or OCF₃ and bond ε is a single bond, or-   R₇ is CH₂ and bond ε is a double bond;-   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH,    or OCF₃;-   R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a single    bond;-   R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy or    methane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and    R₁₆ are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ    is a single bond;-   R₁₁ together with R₁₂ and the carbons to which each is attached to    form an oxirane moiety form an ether group and bond δ is a single    bond; or-   R₁₁ and R₁₂ are absent and bond δ is a double bond.

In one embodiment, the compound has the structure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆, and R₇ are CH₃, and R₃ is p-toluene sulfonyloxy.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆, and R₇ are CH₃, R₃ is p-toluene sulfonyloxy and R₄ is I, Br,Cl, or Si(CH₃)₃.

In another embodiment, the compound has the structure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, and R₅ isOSi(CH₃)₃.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl,or Si(CH₃)₃, and R₅ is OSi(CH₃)₃.

In another embodiment, the compound has the structure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy and R₅ isOSi(CH₃)₃.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl,or Si(CH₃)₃, and R₅ is OSi (CH₃)₃.

In yet another embodiment, the compound has the structure of formula

In an embodiment of the preceding formula, R₁, R₂, R₆, and R₇ are CH₃,R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃, R₈, R₉, R₁₀,and R₁₁ are H, and R₁₂ is R_(1s) R₁₆Si, wherein R₁₅ and R₁₆ are eachindependently (C₁-C₄)alkyl or Ph.

In another embodiment of the preceding formula, R₁, R₂, R₆, and R₇ areCH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si (CH₃)₃, R₈, R₉,R₁₀, and R₁₁ are H, and R₁₂ is OH.

In another embodiment, the compound has the structure of formula

In an embodiment of the preceding formula, R₁, R₂, R₆, and R₇ are CH₃,R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃, R₅ isOSi(CH₃)₃, R₈, R₉, R₁₀, and R₁₁ are H, and R₁₂ is OH.

The subject application also provides for a compound having thestructure of the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄)alkyl.

In an embodiment of the preceding formula, R₁, R₂, R₆, and R₇ are CH₃,R₃ is p-toluene sulfonyloxy, R₄, R₈, R₉ and R₁₀ are H, and R₁₃ isC(O)SCH₂CH₃.

In another embodiment of the preceding formula, R₁, R₂, R₆, and R₇ areCH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br Cl, or Si(CH₃)₃, R₈, R₉and R₁₀ are H, and R₁₃ is C(O)SCH₂CH₃.

In yet another embodiment of the preceding formula, R₁, R₂, R₆, and R₇are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br Cl, or Si(CH₃)₃, R₈,R₉ and R₁₀ are H, and R₁₃ is C(O)OH.

In another embodiment, a compound having the structure

The subject application also provides for a composition comprising acompound having the structure of the formula

wherein,

-   R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃,-   R₂ is H, (C₁-C₄) alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃;-   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl,    or OC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a    double bond or-   R₃ is O, bond α is a double bond and bond β is a single bond;-   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;-   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single    bond, or-   R₅ is O and bond γ is a double bond;-   R₆ is H, (C₁-C₄) alkyl, or CF₃;-   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide,    CH₂OCF₃ or OCF₃ and bond ε is a single bond, or-   R₇ is CH₂ and bond ε is a double bond;-   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH,    or OCF₃;-   R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a single    bond;-   R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy or    methane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and    R₁₆ are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ    is a single bond;-   R₁₁ together with R₁₂ and the carbons to which each is attached to    form an oxirane moiety form an ether group and bond δ is a single    bond; or-   R₁₁ and R₁₂ are absent and bond δ is a double bond; and wherein the    composition is free of biological material of illicium tashiroi.

In an embodiment of the preceding formula, the compound has thestructure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆, and R₇ are CH₃, and R₃ is p-toluene sulfonyloxy.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆, and R₇ are CH₃, R₃ is p-toluene sulfonyloxy and R₄ is I, Br,Cl, or Si(CH₃)₃.

In yet another embodiment, the compound has the structure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, and R₅ isOSi(CH₃)₃.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl,or Si(CH₃)₃, and R₅ is OSi (CH₃)₃.

In yet another embodiment, the compound has the structure of the formula

In an embodiment of the preceding formula, R₁, R₄, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy and R₅ isOSi(CH₃)₃.

In another embodiment of the preceding formula, R₁, R₈, R₉, and R₁₀ areH, R₂, R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl,or Si(CH₃)₃, and R₅ is OSi (CH₃)₃.

In another embodiment, the compound has the structure of formula

In an embodiment of the preceding formula, R₁, R₂, R₆, and R₇ are CH₃,R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si (CH₃)₃, R₈, R₉, R₁₀,and R₁₁ are H, and R₁₂ is R₁₅R₁₆Si, wherein R₁₅ and R₁₆ are eachindependently (C₁-C₄)alkyl or Ph.

In another embodiment of the preceding formula, R₁, R₂, R₆, and R₇ areCH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si (CH₃)₃, R₈, R₉,R₁₀, and R₁₁ are H, and R₁₂ is OH.

In another embodiment of the preceding formula, the compound has thestructure of formula

In an embodiment of the preceding formula, R₁, R₂, R₆, and R₇ are CH₃,R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃, R₅ isOSi(CH₃)₃, R₈, R₉, R₁₀, and R₁₁ are H, and R₁₂ is OH.

The subject application also provides for a composition comprising acompound having the structure of the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄) alkyl.

In another embodiment of the preceding formula, R₁, R₂, R₆, and R₇ areCH₃, R₃ is p-toluene sulfonyloxy, R₄, R₈, R₉ and R₁₀ are H, and R₁₃ isC(O)SCH₂CH₃.

In yet another embodiment of the preceding formula, R₁, R₂, R₆, and R₇are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br Cl, or Si (CH₃)₃, R₈,R₉ and R₁₀ are H, and R₁₃ is C(O)SCH₂CH₃.

In still another embodiment of the preceding formula, R₁, R₂, R₆, and R₇are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br Cl, or Si (CH₃)₃, R₈,R₉ and R₁₀ are H, and R₁₃ is C(O)OH.

The subject application also provides for a compound having thestructure of formula

-   -   wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃;    -   R₁₉ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₀ is H, p-toluene sulfonyloxy, methane sulfonyloxy,        C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, and bond α is a single        bond or R₂₀ is O and bond α is a double bond;    -   R₂₁, R₂₄, and R₂₅ are each independently H, O(C₁-C₄)alkyl,        (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₂ is a halide, H, or (C₁-C₄)alkyl; and    -   R₂₃ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph.

In another embodiment of the preceding formula, R₁₈, R₁₉ and R₂₃ areCH₃, R₂₀ is p-toluene sulfonyloxy and bond α is a single bond, R₂₁, R₂₄and R₂₅ are H, and R₂₂ is Br.

In yet another embodiment of the preceding formula, R₁₈, R₁₉ and R₂₃ areCH₃, R₂₀ is O and bond α is a double bond, R₂₁, R₂₄ and R₂₅ are H, andR₂₂ is Br.

In another embodiment, the compound has the structural formula

The subject application also provides for a process of producing acompound of the formula

-   -   wherein,    -   R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃;    -   R₂ is H, (C₁-C₄)alkyl, halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or        OCF₃;    -   R₃ is p-toluene sulfonyloxy, methane sulfonyloxy,        C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, bond α is a single bond        and bond β is a double bond, or    -   R₃ is O, bond α is a double bond and bond β is a single bond;    -   R₄ is H, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃;    -   R₅ is OH, OSi(CH₃)₃, O(C₁-C₄)alkyl, or OCF₃, and bond γ is a        single bond, or    -   R₅ is O and bond γ is a double bond;    -   R₆ is H, (C₁-C₄)alkyl, or CF₃;    -   R₇ is H, OH, (C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH,        halide, CH₂OCF₃ or OCF₃ and bond ε is a single bond, or    -   R₇ is CH₂ and bond ε is a double bond;    -   R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide,        OH, or OCF₃; and    -   R₁₁ and R₁₂ are each independently H, (C₁-C₄)alkyl, halide, OH,        or OCF₃ and bond δ is a single bond,    -   R₁₁ together with R₁₂ and the carbons to which each is attached        to form an oxirane moiety form an ether group and bond δ is a        single bond or    -   R₁₁ and R₁₂ are absent and bond δ is a double bond,        comprising subjecting a compound of the formula

-   -   wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₀, and R₁₁ are defined as        above; and    -   R₁₃ is —C(O)OH, —C(O)O(C₁-C₄)alkyl, or —C(O)S(C₁-C₄)alkyl,        to a tandem oxidative dearomatization-transannulation        Diels-Alder reaction to obtain the compound.

In an embodiment of the preceding process, the tandem oxidativedearomatization-transannulation Diels-Alder reaction comprises reactinga compound of the formula

with phenyliodine(III)diacetate (PIDA) to obtain a compound of theformula

In an embodiment of the preceding process, further comprising subjectingthe compound of the formula

to a ring closure reaction to obtain the compound of the formula

In an embodiment of the preceding process, the ring closure reactioncomprises hydrochloric acid.

In an embodiment of the process of the subject invention, the processfurther comprising

-   -   a) reducing the compound of the formula

-   -   -   to obtain a compound of the formula

-   -   -   -   wherein            -   MOM is CH₂OCH₃;            -   R₁₄ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, or R₁₅R₁₆Si,                wherein R₁₅ and R₁₆ are each independently (C₁-C₄)alkyl,                furanyl or Ph;            -   and            -   R₁₇ is —C(O)O(C₁-C₄)alkyl, —C(O)OH, or —CH₂OH.

In another embodiment of the subject invention, the process furthercomprises the steps of:

-   -   a) reacting a compound of the formula

-   -   -   wherein MOM is CH₂OCH₃,        -   with Bestmann reagent, and K₂CO₃ to obtain a compound of the            formula

-   -   b) reacting the product of step a) sequentially with        -   i) n-butyl lithium and CO₂,        -   ii) 1-[3-(dimethylamino)propyl]-3-ethylcarbiimide            hydrochloroide (EDCI), (C₁-C₄)alkyl mercaptan or            (C₁-C₄)alkyl alcohol, dimethylaminopyridine (DMAP), and            4-(dicyanomethene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran            (DCM), and        -   iii) hydrochloric acid        -   to obtain a compound of the formula

In an embodiment of the of the subject invention, further comprising thecompound of the formula

-   -   a) reacting with lithium diisoproplyamine (LDA) and methyl        iodide to obtain a compound of the formula

-   -   b) reacting the product step a) sequentially with        -   i) H₂, Pd/C,        -   ii) 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one            (Dess-Martin reagent),        -   iii) lithium diisoproplyamine and H+, and        -   iv) NH₂NH₂ and NaOH        -   to obtain a compound of the formula

-   -   c) reacting the product of step b) with        -   i) (CH₃CH₂)₃SiH and Pd/C, and        -   ii) 9-borabicyclo[3.3.1]nonane-pyridine(9-BBN-pyr) or            diisobutylaluminum hydride (DIBAL-H)        -   to obtain a compound of the formula

-   -   d) reacting the product of step c) with aqueous hydrochloric        acid to obtain a compound of the formula

-   -   e) reacting the product of step d) with a suitable source of        hydride ion then a trimethylsilane (TMS) halide to obtain a        compound of the formula

-   -   f) reacting the product of claim e) with m-chloroperoxybenzoic        acid (mCPBA) to obtain a compound of the formula

-   -   -   and

    -   g) reacting the product of step f) with a suitable source of        hydride ion and a suitable source of hydroxide ion,        to thereby obtain the compound.

In another embodiment of the of the subject invention, furthercomprising the compound of the formula

-   -   a) reacting with lithium diisoproplyamine (LDA) and methyl        iodide to obtain a compound of the formula

-   -   b) reacting the product step a) with BH₃ in tetrahydrofuran        (THF)        -   to obtain a compound of the formula

-   -   c) reacting the product of step b) with hydrochloric acid to        obtain a compound with the formula

-   -   d) reacting the product of step c) with        -   i) a suitable source of hydride ion, and        -   ii) trimethylsilyl chloride (TMSCl)        -   to obtain a compound of the formula

-   -   e) reacting the product of claim d) with m-chloroperoxybenzoic        acid (mCPBA) to obtain a compound of the formula

-   -   -   and

    -   f) reacting the product of step e) with a suitable source of        hydride ion and a suitable source of hydroxide ion,        to thereby obtain the compound.

In yet another embodiment of the of the subject invention, furthercomprising the compound of the formula

-   -   a) reacting with lithium diisoproplyamine (LDA) and methyl        iodide to obtain a compound of the formula

-   -   b) reacting the product step a) with        -   i) (CH₃CH₂)₃SiH, Pd/C 10% and        -   ii) a suitable source of hydride ion        -   to obtain a compound of the formula

-   -   c) reacting the product of step b) with aqueous hydrochloric        acid to obtain a compound of the formula

-   -   d) reacting the product of step c) with hydride ion and        trimethylsilyl chloride (TMSCl) to obtain a compound of the        formula

-   -   e) reacting the product of claim d) with m-chloroperoxybenzoic        acid (MCPBA) to obtain a compound of the formula

-   -   -   and

    -   f) reacting the product of step e) with a suitable source of        hydride ion and a suitable source of hydroxide ion,        to thereby obtain the compound.

In an embodiment of the of the subject invention, further comprising thecompound of the formula

-   -   a) reacting with a suitable source of hydride ion and        hydrochloric acid to obtain a compound of the formula

-   -   b) reacting the product of step a) with phenyliodine (III)        diacetate (PIDA) according to a tandem oxidative        dearomatization-transannular Diels-Alder reaction to obtain a        compound of the formula

-   -   c) reacting the product of step b) with hydrogen peroxide,        (C₁-C₄)alkyl peroxide or benzyl peroxide and NaOH to obtain a        compound of the formula

-   -   d) reacting the product of step c) with a suitable source of        hydride ion to obtain a compound of the formula

-   -   e) reacting the product of step d) with a suitable source of        hydroxide ion        to thereby obtain the compound.

In an embodiment, the subject application provides for a process toproduce the compound having the formula

-   -   wherein R₁ is H or OBz,        comprising:    -   a) reacting a compound with the formula

-   -   -   wherein R′ is H or OBn;        -   MOM is CH₂OCH₃;        -   Me is CH₃; and        -   Ts is p-toluene sulfonyl,

    -   with Bestmann reagent, and K₂CO₃ to obtain a compound of the        formula

-   -   b) reacting the product of step a) sequentially with        -   i) n-butyl lithium and CO₂,        -   ii) 1-[3-(dimethylamino)propyl]-3-ethylcarbiimide            hydrochloroide (EDCI), (C₁-C₄)alkyl mercaptan or            (C₁-C₄)alkyl alcohol, dimethylaminopyridine (DMAP), and            4-(dicyanomethene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran            (DCM), and        -   iii) hydrochloric acid        -   to obtain a compound of the formula

-   -   -   -   wherein EtSOC is —CH₃CH₂S(O)C;

    -   c) subjecting the product of step b) to the tandem oxidative        dearomatization-transannular Diels-Alder reaction using        phenyliodine (III)diacetate (PIDA) to obtain a compound of the        formula

-   -   d) reacting the product of step c) with lithium diisoproplyamine        (LDA) and methyl iodide to obtain a compound of the formula

-   -   e) reacting the product of step d) sequentially with        -   i) H₂, Pd/C,        -   ii) 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one            (Dess-Martin reagent),        -   iii) lithium diisoproplyamine (LDA) and H⁺, and        -   iv) NH₂NH₂ and NaOH        -   to obtain a compound of the formula

-   -   f) reacting the product of step e) with        -   i) (CH₃CH₂)₃SiH and Pd/C, and        -   ii) 9-borabicyclo[3.3.1]nonane-pyridine(9-BBN-pyr) or            diisobutylaluminum hydride (DIBAL-H)        -   to obtain a compound of the formula

-   -   g) reacting the product of step f) with aqueous hydrochloric        acid to obtain a compound of the formula

-   -   h) reacting the product of step g) with a suitable source of        hydride ion then a trimethylsilane (TMS) halide to obtain a        compound of the formula

-   -   -   wherein TMSO is OSi(CH₃)₃;

    -   i) reacting the product of step h) with m-chloroperoxybenzoic        acid (MCPBA) to obtain a compound of the formula

-   -   j) reacting the product of step i) with a suitable source of        hydride ion and a suitable source of hydroxide ion        to thereby obtain the compound.

In another embodiment, the subject application provides for a process toproduce the compound having the formula

-   -   wherein R₁ is H or OBz,        comprising:    -   a) reacting a compound with the formula

-   -   -   wherein MOM is CH₂OCH₃;        -   Me is CH₃; and        -   Ts is p-toluene sulfonyl,

    -   with Bestmann reagent, and K₂CO₃ to obtain a compound of formula

-   -   b) reacting the product of step a) sequentially with        -   i) n-butyl lithium and CO₂,        -   ii) n-iodosuccinamide (NIS) or n-bromosuccinamide (NBS) or            n-chlorosuccinamide (NCS) or trimethylsilyl-trimethylsilyl            (TMS-TMS), and Pd and        -   iii) hydrochloric acid        -   to obtain a compound of the formula

-   -   -   -   wherein X is I, Br, Cl, or Si(CH₃)₃;

    -   c) subjecting the product of step b) to the tandem oxidative        dearomatization-transannular Diels-Alder reaction using        phenyliodine (III)diacetate (PIDA) to obtain a compound of the        formula

-   -   d) reacting the product of step c) with lithium diisoproplyamine        (LDA) and methyl iodide to obtain a compound of the formula

-   -   e) reacting the product of step d) with BH₃ in tetrahydrofuran        (THF)        -   to obtain a compound of the formula

-   -   f) reacting the product of step e) with hydrochloric acid to        obtain a compound with the formula

-   -   g) reacting the product of step f) with        -   i) a suitable source of hydride ion, and        -   ii) trimethylsilyl chloride (TMSCl)        -   to obtain a compound of the formula

-   -   -   -   wherein TMSO is OSi(CH₃)₃;

    -   h) reacting the product of step g) with m-chloroperoxybenzoic        acid (mCPBA) to obtain a compound of the formula

-   -   i) reacting the product of step h) with a suitable source of        hydride ion and a suitable source of hydroxide ion        to thereby obtain the compound.

In an embodiment, the subject application provides for a process toproduce the compound having the formula

-   -   wherein R₁ is H or OBz,        comprising:    -   a) reacting a compound with the formula

-   -   -   wherein MOM is CH₂OCH₃;        -   Me is CH₃; and        -   Ts is p-toluene sulfonyl,

    -   with Bestmann reagent, and K₂CO₃ to obtain a compound of formula

-   -   b) reacting the product of step a) sequentially with        -   i) n-butyl lithium and CO₂,        -   ii) 1-[3-(dimethylamino)propyl]-3-ethylcarbiimide            hydrochloroide (EDCI), (C₁-C₄)alkyl mercaptan or            (C₁-C₄)alkyl alcohol, dimethylaminopyridine (DMAP), and            4-(dicyanomethene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran            (DCM),        -   iii) n-iodosuccinamide (NIS) or n-bromosuccinamide (NBS) or            n-chlorosuccinamide (NCS) or trimethylsilyl-trimethylsilyl            (TMS-TMS), and Pd and        -   iv) hydrochloric acid        -   to obtain a compound of the formula

-   -   -   -   wherein EtSOC is —CH₃CH₂S(O)C; and            -   X is I, Br, Cl, or Si(CH₃)₃;

    -   c) subjecting the product of step b) to the tandem oxidative        dearomatization-transannular Diels-Alder reaction using        phenyliodine (III)diacetate (PIDA) to obtain a compound of the        formula

-   -   d) reacting the product of step c) with lithium diisoproplyamine        (LDA) and methyl iodide to obtain a compound of the formula

-   -   e) reacting the product of step d) with        -   i) (CH₃CH₂)₃SiH and Pd/C; and        -   ii) a suitable source of hydride ion        -   to obtain a compound of the formula

-   -   f) reacting the product of step e) with aqueous hydrochloric        acid to obtain a compound of the formula

-   -   g) reacting the product of step f) with hydride ion and        trimethylsilyl chloride (TMSCl) to obtain a compound of the        formula

-   -   h) reacting the product of step g) with m-chloroperoxybenzoic        acid (mCPBA) to obtain a compound of the formula

-   -   -   wherein TMSO is OSi(CH₃)₃;

    -   i) reacting the product of step h) with        -   i) a suitable source of hydride ion and a suitable source of            hydroxide ion and        -   ii) Zn or (PhSe)₂ or NaI,            to thereby obtain the compound.

In yet another embodiment, the subject application provides for aprocess to produce the compound having the formula

-   -   wherein R₁ is H or OBz,        comprising:    -   a) reacting a compound with the formula

-   -   -   wherein MOM is CH₂OCH₃;        -   Me is CH₃; and        -   Ts is p-toluene sulfonyl,

    -   with Bestmann reagent, and K₂CO₃ to obtain a compound of the        formula

-   -   b) reacting the product of step a) sequentially with        -   i) n-butyl lithium and CO₂,        -   ii) 1-[3-(dimethylamino)propyl]-3-ethylcarbiimide            hydrochloroide (EDCI), (C₁-C₄)alkyl mercaptan or            (C₁-C₄)alkyl alcohol, dimethylaminopyridine (DMAP), and            4-(dicyanomethene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran            (DCM),        -   iii) n-iodosuccinamide (NIS) or n-bromosuccinamide (NBS) or            n-chlorosuccinamide (NCS) or trimethylsilyl-trimethylsilyl            (TMS-TMS), and Pd and        -   iv) hydrochloric acid        -   to obtain a compound of the formula

-   -   -   -   wherein R₂₈ is (C₁-C₄)alkyl; and            -   X is I, Br, Cl, or Si(CH₃)₃;

    -   c) reacting the product of step b) with        -   i) R₁₆R₁₅SiCuLi and I₂ and        -   ii) Me₄Sn and Pd,        -   to obtain a compound of the formula

-   -   -   -   wherein R is (C₁-C₄)alkyl; and            -   R₁₅ and R₁₆ are each independently (C₁-C₄)alkyl, furanyl                or Ph;

    -   d) reacting the product of step c) with a suitable source of        hydride ion and hydrochloric acid to obtain a compound of the        formula

-   -   e) subjecting the product of step d) to the tandem oxidative        dearomatization-transannular Diels-Alder reaction using        phenyliodine (III)diacetate (PIDA) to obtain a compound of the        formula

-   -   f) reacting the product of step e) with hydrogen peroxide,        (C₁-C₄)alkyl peroxide or benzyl peroxide and NaOH to obtain a        compound of the formula

-   -   g) reacting the product of step f) a suitable source of hydride        ion to obtain a compound of the formula

-   -   h) reacting the product of step g) with a suitable source of        hydroxide ion and HCl        to thereby obtain the compound.

The subject application also provides for a process of producing acompound of the formula

-   -   wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃;    -   R₁₉ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₀ is H, p-toluene sulfonyloxy, methane sulfonyloxy,        C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, bond α is a single bond        and bond β is a double bond or    -   R₂₀ is O, bond α is a double bond and bond β is a single bond;    -   R₂₁, R₂₄, and R₂₅ are each independently H, O(C₁-C₄)alkyl,        (C₁-C₄)alkyl, halide, OCF₃, or CF₃;    -   R₂₂ is a halide, H, or (C₁-C₄)alkyl; and    -   R₂₃ is H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph        comprising reacting a compound of the formula

with a compound of the formula

to obtain the compound.

The subject application also provides for a compound produced by any oneof the preceding processes.

The subject application also provides for a pharmaceutical compositioncomprising any one of the preceding compounds or compositions and apharmaceutically acceptable carrier.

The subject invention also provides a process of producing a compound ofthe formula

-   -   comprising        -   a) reacting the compounds of the formulae

-   -   wherein R₁ are defined as above, with Pd₂(dba)₃, ^(t)Bu₃P, and        DMF to obtain a compound of the formula

-   -   -   b) reacting the product of step a) with DMP and DCM to            obtain a compound of the formula

-   -   -   c) reacting the product of step b) with a compound of the            formula

-   -   BuLi, and THF to obtain a compound of the formula

-   -   -   d) reacting the product of step c) first with MsCl and TEA            and then with Me₂Cu(CN)Li₂ to obtain a compound of the            formula

-   -   -   e) reacting the product of step d) with TBAF and THF to            obtain a compound of the formula

-   -   -   f) and reacting the product of step e) with PIDA and Toluene            to thereby obtain the compound.

The subject invention further provides a process of producing a compoundof the formula

-   -   comprising        -   b) reacting a compound of the formula

with NaBH₄ and MeOH to produce a compound of the formula

-   -   -   b) reacting the product of step a) with TMS-Imid to produce            a compound of the formula

-   -   -   c) reacting the product of step b) with mCPBA and DCM to            produce a compound of the formula

-   -   -   d) reacting the product of step c) with H₂, Pd/C 5%, and            EtOAc to produce a compound of the formula

-   -   -   e) reacting the product of step d) with an acid in water to            thereby obtain the compound.

Throughout this application the abbreviation “Bz” is used to refer tobenzene and the abbreviation “Bn” is used to refer to benzyl.

Discussion

The subject invention provides a free-standing synthetic route as analternative to the complexities of obtaining either 1 or 2 from naturalsources. The synthetic route also provides a diverted total synthesis toexplore tashironin analogs.

One approach to constructing the structural backbone ofdebenzoyltashironin employed a tandem oxidativedearomatization-transannular Diels-Alder reaction to rapidly generatethe highly substituted tetracyclic core 5 from a relatively simpleprecursor 4 (Scheme 1). According to our design, the key substrate 4 isprepared from a suitably protected aromatic precursor 3.

We noted that under suitable reaction conditions, 4 can undergointramolecular oxidative dearomatization, following the protocol ofPelter and Tamura (Pelter, et al., Tetrahedron Lett. 1988, 29, 677;Tamura, et al., Org. Chem. 1987, 52, 3927; Magdziak, et al., Chem. Rev.2004, 104, 1383.) to give rise to an intermediate cyclized species thatcan be configured to undergo a transannular Diels-Alder reaction toafford 5 which in turn can be progressed to 1. Success of this strategyis predicated on the ability of the methyl stereocenter in the tandemprecursor 4 to exert diastereofacial control in the oxidativedearomatization step.

EXPERIMENTAL DETAILS Example 1 Formation of the Tetracyclic Core

Our synthesis commenced with commercially available vanillyl alcohol 3a.Compound 3a was treated with catalytic amounts of tosyl acid in methanolto afford 3b, presumably via a p-quinone methide intermediate (Scheme2). The aromatic methyl group was then installed regiospecifically atthe more hindered site through directed lithiation followed bymethylation to afford 6. A subsequent2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated oxidation gaverise to 2-methylvanillin 7 in 44% overall yield from 3a. Crotylation ofthe phenolic hydroxyl group, followed by a Claisen rearrangementproduced phenol 8. For greater flexibility in later transformations, thephenol was protected either as a benzyl ether 9a or as a MOM ether 9b.Baeyer-Villiger oxidation of these compounds followed by hydrolysisafforded phenols 10a and 10b in 54% and 95% overall yields,respectively, from 8. The resultant phenolic hydroxyl group in eachcompound was then tosylated to produce 11a and 11b in the yields shown.These compounds were hydroformylated with acetyl acetonate dicarbonylrhodium (1) (Rh(CO)₂(acac)) and the Billig bis-organophosphite ligandaccording to Buchwald's protocol, to give exclusively the desired linearaldehydes 12a and 12b in 90% and 82% yields, respectively (Cuny, et al.,J. Am. Chem. Soc. 1993, 115, 2066).

At this juncture, we tested the feasibility of our key transformation.Toward this end, subjection of aldehyde 12a to Roskamp conditionsfollowed by methylation of the resulting β-ketoester gave rise to 13(Scheme 3) (Holmquist, et al., J. Org. Chem. 1989, 54, 3258). Treatmentof 13 with methanesulfonyl chloride and triethylamine (TEA) in methylenechloride led to the formation of the desired (E)-tetrasubstituted olefin14 in modest yield. Olefin geometry was determined by Nuclear OverhauserEffect (NOE) studies of the reduced product. Finally, reduction of theethyl ester with diisobutylaluminium hydride (DIBAL-H), followed bybenzyl deprotection gave the key substrate, 15.

In the event, treatment of 15 with phenyliodine(III) diacetate (PIDA,PhI(OAc)₂) in a toluene/acetonitrile solvent system gave rise cleanly toa new product, 16, which was quite unstable. Alternatives to PIDA areother hypervalent iodine compounds such asphenyliodine(III)bis(trifluoroacetate) (PIFA), phenyliodine(III)sulfate,or dichloroiodobenzene. We note that formation of spiro ether 16a byipso spirocyclization is apparently not at all competitive with the metapathway leading from 15 to 16. Such an ipso pathway is inherent in theBecker-Adler reaction and analogs thereof. Evidently, the proclivity forattack at the electron-rich methoxy-bearing carbon is dominant in thePIDA mediated cyclization.

Of course, in reality, for a particular antipode, the methyl groupdefines the absolute configuration of the resultant cage-likelatticework in structure 16. For convenience sake, we portray theintermediate by permuting the relative stereochemistry of the methylbearing carbon.

As shown in Scheme 3, compound 16 failed to undergo the expectedtransannular Diels-Alder reaction (see target structure 17) underseveral sets of conditions. The surprising lability of 16 limited ouroptions for permuting reaction conditions to accomplish transannularDiels-Alder reaction.

The stereoelectronic complexity coupled with the high steric demandrequired of the tetrasubstituted diene in reacting with atetrasubstituted dienophile might be responsible for the resistance of16 to undergo transannular Diels-Alder reaction. Therefore, we sought toexamine the behavior of less complicated putative Diels-Aldersubstrates. Thus, aldehyde 12a was subjected to Still-Gennariolefination conditions with two different phosphonates (Scheme 4)(Still, et al., Tetrahedron Lett. 1983, 24, 4405). The disubstitutedolefin 18 and the trisubstituted olefin 19 were obtained in 52% yieldand 68% yield, both as 10:1-mixtures of (Z)/(E)-geometric isomers.Cleavage of the corresponding benzyl protecting group followed byDIBAL-H reduction of the ester functionalities proceeded smoothly toprovide the key substrates 20 and 21 in 87% and 69% yield, respectively.

Treatment of phenol 20 with PIDA in toluene over several hours at roomtemperature resulted in the formation of the desired transannularDiels-Alder adduct 22 in 66% yield as a single diastereomer, presumablyvia the corresponding 10-membered acetal. Similarly, when phenol 21,containing a trisubstituted double bond, was subjected to identicalconditions, the transannular Diels-Alder adduct 23 was formed in astereoselective fashion in 60% yield. NMR Nuclear Overhauser Effect(NOE) analysis of compound 23 revealed the stereochemistry at C-1, withthe C-15 methyl group residing in the undesired a position. In otherwords, this C-15 methyl had orchestrated the sense of the oxidativecyclization reactions of 20 and 21 so as to produce 20a and 21a. Theseintermediates must, per force, produce the observed intramolecularDiels-Alder (IMDA) products.

Experimental Procedures and Physical Data for Compounds 16, 22, and 23

Cyclic Acetal 16: To a solution of phenol 15 (7.5 mg, 0.014 mmol) intoluene (1 mL) at rt was added a solution of PIDA (5.3 mg, 0.016 mmol)in a 4:1 mixture of toluene:MeCN (1 mL) during 8 h via syringe pump. Thereaction mixture was stirred for an additional 2 h at rt. The resultingclear, yellow solution was then diluted with DCM (30 mL), washed withsaturated aqueous Na₂S₂O₃ (1×30 mL) and saturated aqueous NaHCO₃ (2×30mL), then dried (MgSO₄) and concentrated. Purification by pTLC (1:1hexane:diethyl ether) yielded compound 16 as a slightly yellow film (4.5mg, 60%). ¹H-NMR (300 MHz, CDCl₃) d 7.84 (d, J=8.3, 2H), 7.39 (d, J=8.3,2H), 6.40 (s, 1H), 4.13 (d, J=14.1, 1H), 4.02 (d, J=14.1, 1H), 3.24 (s,3H), 3.12 (s, 3H), 2.86 (m, 1H), 2.48 (s, 3H), 2.36 (m, 1H), 2.11 (m,1H), 1.69 (s, 3H), 1.62 (s, 3H), 1.01 (d, J=6.9, 3H).

Cycloadduct 22: To a solution of phenol 20 (13 mg, 0.031 mmol) intoluene (1 mL) at rt was added a solution of PIDA (13 mg, 0.043 mmol) ina 4:1 mixture of toluene:MeCN (1 mL) during 4 h via syringe pump. At theend of the addition, the reaction was found to be complete. The reactionmixture was concentrated without workup and the residue was purified bypreparatory thin layer chromatography (pTLC) (1:1 hexane:diethyl ether).Compound 22 was isolated as a slightly yellow film (8.5 mg, 66%). ¹H-NMR(300 MHz, CDCl₃) d 7.79 (d, J=8.3, 2H), 7.37 (d, J=8.1, 2H), 5.77 (s,1H), 4.12 (dd, J_(gem)=8.9, J_(vie)=4.2, 1H), 3.76 (d, J=8.9, 1H), 3.51(s, 3H), 2.81 (m, 1H), 2.46 (s, 3H), 2.13 (m, 2H), 1.88 (m, 1H), 1.65(m, 2H), 1.22 (s, 3H), 0.88 (d, J=7.1, 3H); ¹³C-NMR (125 MHz, CDCl₃) d201.66, 148.97, 145.69, 132.63, 129.78, 128.65, 116.95, 100.27, 66.29,60.02, 54.36, 52.50, 47.93, 41.68, 34.26, 27.24, 25.83, 21.72, 18.86,12.26.

Cycloadduct 23: To a solution of phenol 21 (5.4 mg, 0.012 mmol) intoluene (1 mL) at rt was added a solution of PIDA (4.8 mg, 0.015 mmol)in a 4:1 mixture of toluene:MeCN (1 mL) during 4 h via syringe pump. Atthe end of the addition, the reaction was found to be complete. Thereaction mixture was concentrated without workup and the residue waspurified by pTLC (1:1 hexane:diethyl ether). Compound 23 was isolated asa slightly yellow film (3.2 mg, 60%). ¹H-NMR (300 MHz, CDCl₃) d 7.80 (d,J=8.4, 2H), 7.36 (d, J=8.4, 2H), 5.87 (s, 1H), 3.73 (m, 2H), 3.50 (s,3H), 2.80 (m, 1H), 2.46 (s, 3H), 2.14 (m, 1H), 1.62 (m, 1H), 1.52 (m,1H), 1.12 (s, 3H), 0.94 (s, 3H), 0.91 (d, J=7.2, 3H); ¹³C-NMR (125 MHz,CDCl₃) d 202.00, 149.19, 146.08, 133.06, 130.21, 129.10, 116.21, 101.2,72.18, 59.93, 55.63, 55.21, 54.50, 44.68, 34.41, 30.11, 27.65, 25.49,22.13, 19.38, 9.54.

Conclusion

Having shown that both the di- and trisubstituted olefins do indeedundergo stereospecific oxidative dearomatization followed bytransannular Diels-Alder, in contrast to the tetrasubstituted system in16, we proceeded to reduce the complexity of the key sequence: insteadof constructing all four rings of tashironin in a single transformation,we built three of the four rings by the oxidativedearomatization-transannular Diels-Alder cascade and then closing thefourth ring in subsequent transformations. Following this logic, the[2.2.2]bicyclic ring system is formed concomitantly either with thefused cyclopentane ring or with the 5-membered acetal. These approachesare exemplified in Examples 2 and 3.

Example 2 Formation of the Fused Cyclopentane Ring

In one approach, aldehyde 12b was converted to terminal alkyne 24 in 65%yield using the Bestmann reagent (Scheme 5) (Muller, et al., Synlett1996 521; Ohira, Synth. Commun. 1989 19, 561). Phenol 25 was revealed in90% yield after HCl-mediated removal of the MOM group. Exposure ofphenol 25 to PIDA in MeOH at room temperature presumably led to theformation of the corresponding masked o-quinone, which underwent thedesired transannular Diels-Alder reaction upon heating to afford 26diastereoselectively in 85% yield (ds>95%). In the transformation from25 to 26, any alkyl alcohol can be used instead of MeOH.

We were able to obtain single crystals of 26. X-ray analysis led to adecisive structural verification, revealing the relative configurationof the two quarternary stereocenters C-6/C-9 and the tertiarystereocenter C-1 as shown in Scheme 5. Crystallographic data (excludingstructural data) for compound 26 have been deposited with the CambridgeCrystallographic Data Centre (CCDC) as Deposition No. CCDC 230898).

Experimental Procedures and Physical Data for Compound 26

Cycloadduct 26: To a solution of phenol 25 (78 mg, 0.201 mmol) in MeOH(4 mL) at rt was added a solution of PIDA (78 mg, 0.241 mmol) in MeOH(1.5 mL) during 1 h. The reaction mixture was then quenched with amixture of saturated aqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ thendiluted with Et₂O. The organic layer was separated and the aqueous layerwas extracted with Et₂O (3×). The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The residual oil wasdissolved in toluene (6 mL), heated to reflux for 20 min, thenconcentrated under reduced pressure. Purification of the crude productby fractional crystallization (FC) (hexane/EtOAc 2:1) affordedcycloadduct 26 (72 mg, 85%) as a white crystalline solid (de>95%). M.p.67-69° C.; ¹H-NMR (500 MHz, CDCl₃) d 7.76 (d, J=8.3, 2H), 7.33 (d,J=8.1, 2H), 5.77 (s, 1H), 5.56 (t, J=1.7, 1H), 3.33 (s, 3H), 3.25 (s,3H), 2.83-2.77 (m, 1H), 2.45 (s, 3H), 2.33-2.29 (m, 2H), 1.92-1.87 (m,1H), 1.56-1.50 (m, 1H), 1.33 (s, 3H), 0.98 (d, J=7.2, 3H); ¹³C-NMR (125MHz, CDCl₃) d 195.19, 155.65, 150.70, 145.44, 132.63, 129.58, 128.69,127.40, 111.33, 93.00, 67.31, 53.67, 53.51, 53.41, 34.72, 31.22, 26.54,21.67, 15.80, 12.16; MS (ESI) 441 [M+Na⁺]; HRMS (FAB) calcd. forC₂₂H₂₆O₆SNa [M+Na⁺] 441.1348, found 441.1347.

Conclusion

The completion of the synthesis of debenzoyltashironin through thisroute requires the installation of functional handles in the Diels-Alderprecursor to allow for the inversion of the stereochemistry at C-1 aswell as for the closing of the 5-membered acetal.

Example 3 Formation of the 5-Membered Acetal

In an alternate approach, we sought to install the 5-membered acetal inconjunction with the [2.2.2]bicyclic ring system through anintermolecular trapping of an allenyl alcohol by oxidativedearomatization and a subsequent Diels-Alder reaction with the internalolefin of the allenol. This proposed IMDA cycloaddition raised obviousissues of regioselectivity. Although we were confident that the internalolefin of the allene would react preferentially due to the geometry ofthe transition state, predictions as to whether the reaction would givethe desired 5-membered acetal Diels-Alder adduct 30 or the 6-memberedacetal (“twisted”) product 29 were less obvious (Scheme 6). In practice,phenol 27 was constructed in nine steps from the commercially availablevanillyl alcohol 3a in 20% overall yield. Following treatment of 27 withPIDA in the presence of 5 equivalents of allenyl alcohol 28, theundesired “twisted” Diels-Alder adduct 29 was obtained (as shown by NOEstudies) (Scheme 6) (Isaac, et al., J. Chem. Soc. Chem. Comm. 1995,1003).

Experimental Procedures and Physical Data for Compound 29

Cycloadduct 29: To a solution of phenol 27 (25 mg, 0.064 mmol) andallenyl alcohol 28 (27 mg, 0.32 mmol, 5 eq.) in toluene (0.5 mL) at rtwas added a solution of PIDA (36 mg, 0.084 mmol) in 4:1 toluene:MeCN (1mL) during 4 h. The reaction mixture was stirred at rt for an additional4 h, then diluted with CH₂Cl₂ (30 mL), and washed with saturated aqueousNa₂S₂O₃ (1×30 mL) and saturated aqueous NaHCO₃ (1×30 mL). The organiclayer was dried (MgSO₄) and concentrated under reduced pressure.Purification of the crude product by pTLC (hexane/Et₂O 1:1) affordedcycloadduct 29 (20.5 mg, 69%) as a yellow film. ¹H-NMR (300 MHz, CDCl₃)d 7.71 (d, J=8.3, 2H), 7.37 (d, J=8.3, 2H), 5.83 (s, 1H), 4.92 (s, 1H),4.88 (s, 1H), 3.73 (d, J=9.5, 1H), 3.53 (s, 3H), 3.41 (d, J=9.5, 1H),2.48 (s, 3H), 1.27 (s, 3H), 1.07 (s, 3H); ¹³C-NMR (300 MHz, CDCl₃=77.0ppm) d 194.69, 151.28, 151.12, 146.02, 131.59, 129.96, 128.72, 114.96,104.09, 73.93, 69.52, 55.21, 54.03, 45.25, 21.74, 18.05, 8.63; HRMS(FAB) calcd. For C₂₀H₂₁BrO₆Sna [M+H⁺] 469.0321, found 469.0329.

Example 4 Completion of the Synthesis of Debenzoyltashironin

Four different methods of completing the synthesis ofdebenzoyltashironin and other tashironin analogs are shown in Schemes 7A-D.

Experimental Procedures and Physical Data for Compound 31a

Thioether 31a: To a stirring solution of 26a (51 mg, 0.1 mmol) in THF (1mL) at −78° C. was added LDA (115 μL of 1M solution). Reaction becamebright yellow immediately. After 5 min, MeI (31 μL, 0.5 mmol) was addedand the reaction was allowed to warm to room temperature (rt) over 5min. Once at room temperature, the reaction was quenched with saturatedNH₄Cl, taken up in CH₂Cl₂ (˜30 mL), and washed with saturated NH₄Cl(2×30 mL). pTLC (20×20×0.5, 1:1 H:Et2O) yielded 14.3 mg of clearslightly yellow film (46% yield BORSM). ¹H-NMR (300 MHz, CDCl₃) δ 7.79(d, J=8.3, 2H), 7.35 (d, J=8.2, 2H), 5.93 (s, 1H), 5.70 (t, J=2.4, 1H),3.24 (s, 3H), 3.15 (s, 3H), 2.8-2.9 (m), 2.6-2.7 (m, 3H), 2.44 (s, 3H),2.07 (m, 1H), 1.39 (s, 3H), 1.26 (s, 3H), 1.09 (d, J=5.6, 3H).

Example 5 Alternate Formation of Tetracyclic Core

In this synthesis, the bromo methylvanillin was protected withtert-butyldimethylsilane using TBSCl, imidazole, and dimethylaminopyridine (DMAP) in 74% yield. This compound was then treated toBaeyer-Villiger conditions (m-chloroperoxybenzoic acid, mCPBA) to yielda formate that is hydrolyzed with triethylamine (TEA) in methanolicsolvent (MeOH/DCM). The new phenol was then tosylated with TsCl andamine base to yield compound number 80.

Example 6 Alternate Formation of the Carboskeleton of Tashironin

This scheme describes a new sequence to the carboskeleton of tashironinemploying different reaction sequences and compounds than the previouslydescribed schemes. None of the intermediate compounds are expected toyield any specific biological result, but the final compound of thescheme, compound number 98, is an analog of debenzoylatashironin andbased upon its relationship to debenzoyltashironin, compound number 98is expected to have neurotrophic activity. From the beginning, apalladium-mediated “Stille” coupling yielded a new primary alcohol thatwas oxidized to a beta,gamma-unsaturated aldehyde in 98% and 99% yield,respectively. Base-mediated (BuLi) alkyne addition to this aldehyde,followed by mesylation of the resulting alcohol (MsCl and TEA) andcuprate addition of a higher-order cyano cuprate (also known as aLipshutz cuprate) yielded a racemic allene. This allene is deprotectedusing tetrabutyl ammonium fluoride (TBAF) in acetic acid to yield ahydroxyphenol. This hydroxyphenol is the key intermediate for thesynthesis. When this hydroxyphenol was subjected tophenyliodo(diacetate) (PIDA), a 12-membered acetal ring was formed insitu, followed by a transannular-Diels-Alder reaction to get thecarboskeleton of tashironin (the last compound of the scheme).

Example 7 Alternate Route to Natural Product and Formation of Analogs

This scheme describes a series of analogs en route to the naturalproduct. Reduction of the ketone produced a secondary alcohol with a 7:1diastereoselectivity. This selectivity can be adjusted experimentally bychanging the nature of the reducing agent. Sodium borohydride gives 7:1,while lithium aluminum hydride provides a 1:1 mixture. Protection ofthis secondary alcohol with trimethylsilane was done in a 1:1 mixture ofTMS-imidazole:CH₂Cl₂. A solvent system containing less TMS-imidazoleresulted in a sluggish reaction. Once protected with trimethylsilane,one of the three double bonds was selectively epoxidized on the faceopposite the TMS protecting group. The exomethylene was thendiastereoselectively reduced using standard hydrogen and palladium oncarbon conditions. Again, the selectivity is accomplished by stericocclusion by the TMS group on the “top” surface of the olefins. Theepoxide was then reductively opened and the tosyl enol ether reductivelycleaved using lithium di-tert-butyldiphenyl (LiDBB) to yield the moresubstituted alcohol and a ketone, respectively. (There exist conditionsthat would result in the opening of epoxide to yield the lesssubstituted alcohol.) Strong acids then remove the remaining TMS and Meprotecting groups to yield the purported neurotrophic factor,debenzoyltashironin.

Since the methyl group of the OMe was so difficult to remove using thechemistry described in this scheme, additional chemistry is described inScheme 8B above that describes a method for incorporating a more labileprotecting group (methyl methoxyether (MOM) is described in scheme 8B).Starting from commercially available methyl catechol, dimethyl sulfatewas used to methylate the two phenols. N-Bromosuccinamide (NBS) inacetonitrile (MeCN) was then used to brominate the aromatic ring at the4-position. Lithium-halogen exchange with butyl lithium (BuLi), followedby quenching with dimethylformamide (DMF) yielded the 4-aldehyde. Borontribromide (BBr₃) removal of the methyl groups revealed the catecholonce again. Here, selective protection of one or the other phenol ispossible. In Scheme 8A, TBS and MOM are used, but just about anycombination would be acceptable. Once protected, another aromaticbromination was carried out using bromine in acetic acid to yield thebromide described in Scheme 8A, albeit with a more labile protectinggroup than methyl.

Discussion

We have shown herein the highly concise synthesis of the tetracyclicring system that forms the core of 11-0-debenzoyltashironin. Thesynthesis was achieved by a Pelter-Tamura oxidation resulting in thetrapping of a tethered allylic alcohol, followed by a transannularDiels-Alder reaction. We have also shown that this reaction sequence isviable for the efficient construction of related, rather complex[2.2.2]-bicyclic compounds.

The synthesis of the [2.2.2]-bicyclic core of the neurotrophic factor11-0-debenzoyltashironin (1) has been achieved by an oxidativedearomatization-transannular Diels-Alder cascade. The reaction sequenceis also valuable for the efficient construction of related, complex[2.2.2]-bicyclic compounds.

The tandem oxidative dearomatization-transannular Diels-Alder reactionsequence is used in any one of four different methods to complete thesynthesis of debenzoyltashironin and tashironin analogs.

Using the aforementioned processes produces Tashironin,debenzoyltashironin and other tashironin derivative compositions free ofbiological material of illicium tashiroi, which biological material isotherwise necessarily present, if only in trace amounts, when tashironinis isolated from the tashiroi plant. Thus, a composition “free” ofbiological material of illicium tashiroi according to this inventioncontains absolutely no such biological material.

Tashironin can be used to treat cancer patients alone or in combinationwith other therapeutic agents. Some patients undergoing treatment withanticancer agents experience a tingling sensation. The tingling has beenattributed to damage to neurites, which damage is possibly caused by theanticancer agents. In the past, Granulocyte Colony Stimulating Factor(GCSF) has been used with chemotherapy to treat patients experiencingthis type of tingling. Thus, it is beneficial to administer tashironinor its derivatives to patients undergoing chemotherapy in an amounteffective to treat or inhibit the damage to neurites associated withchemotherapy.

Tashironin can be used to treat patients with diabetes alone or incombination with other therapeutic agents. Some diabetes patientsexperience a tingling sensation. The tingling has been attributed todamage to neurites, which damage is possibly caused by the diabetes.Thus, it is beneficial to administer tashironin or its derivatives topatients with diabetes in an amount effective to treat or inhibit thedamage to neurites associated with diabetes.

1. A compound having the structure of the formula

wherein, R₁ is H or Bz when no more than three of R₈, R₉, R₁₀ and R₁₁are H, or R₁ is Bn, (C₁-C₄) alkyl, or CF₃; R₂ is H, (C₁-C₄) alkyl,halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃; R₃ is p-toluenesulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl, orOC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a double bondor R₃ is O, bond α is a double bond and bond β is a single bond; R₄ isH, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃, R₅ is OH, OSi(CH₃)₃,O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single bond, or R₅ is O andbond γ is a double bond; R₆ is H, (C₁-C₄) alkyl, or CF₃; R₇ is H, OH,(C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide, CH₂OCF₃ or OCF₃and bond ε is a single bond, or R₇ is CH₂ and bond ε is a double bond;R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH, orOCF₃; R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a singlebond; R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy ormethane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and R₁₆are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ is asingle bond; R₁₁ together with R₁₂ and the carbons to which each isattached to form an oxirane moiety form an ether group and bond δ is asingle bond; or R₁₁ and R₁₂ are absent and bond δ is a double bond. 2.The compound of claim 1 having the structure of the formula


3. The compound of claim 2, wherein R₁, R₄, R₈, R₉, and R₁₀ are H, R₂,R₆, and R₇ are CH₃, and R₃ is p-toluene sulfonyloxy.
 4. The compound ofclaim 2, wherein R₁, R₈, R₉, and R₁₀ are H, R₂, R₆, and R₇ are CH₃, R₃is p-toluene sulfonyloxy and R₄ is I, Br, Cl, or Si(CH₃)₃.
 5. Thecompound of claim 1 having the structure of the formula


6. The compound of claim 5, wherein R₁, R₄, R₈, R₉, and R₁₀ are H, R₂,R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy, and R₅ iS OSi(CH₃)₃. 7.The compound of claim 5, wherein R₁, R₈, R₉, and R₁₀ are H, R₂, R₆ andR₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃,and R₅ is OSi(CH₃)₃.
 8. The compound claim 1 having the structure of theformula


9. The compound of claim 8, wherein R₁, R₄, R₈, R₉, and R₁₀ are H, R₂,R₆ and R₇ are CH₃, R₃ is p-toluene sulfonyloxy and R₅ is OSi(CH₃)₃. 10.The compound of claim 8, wherein R₁, R₈, R₉, and R₁₀ are H, R₂, R₆ andR₇ are CH₃, R₃ is p-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃,and R₅ is OSi(CH₃)₃.
 11. The compound of claim 1 having the structure offormula


12. The compound of claim 11, wherein R₁, R₂, R₆, and R₇ are CH₃, R₃ isp-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃, R₈, R₉, R₁₀, andR₁₁ are H, and R₁₂ is R₁₅R₁₆Si, wherein R₁₅ and R₁₆ are eachindependently (C₁-C₄)alkyl or Ph.
 13. The compound of claim 1 having thestructure of formula


14. The compound of claim 13, wherein R₁, R₂, R₆, and R₇ are CH₃, R₃ isp-toluene sulfonyloxy, R₄ is I, Br, Cl, or Si(CH₃)₃, R₅ is OSi(CH₃)₃,R₈, R₉, R₁₀, and R₁₁ are H, and R₁₂ is OH.
 15. The compound of claim 1,having the structure


16. A pharmaceutical composition comprising the compound of any one ofclaim 1 and a pharmaceutically acceptable carrier.
 17. A compound havingthe structure of the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄) alkyl.
 18. Acomposition comprising a compound having the structure of the formula

wherein, R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃, R₂ is H, (C₁-C₄) alkyl,halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃; R₃ is p-toluenesulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl, orOC(O)(C₁-C₄)alkyl, bond α is a single bond, and bond β is a double bondor R₃ is O, bond α is a double bond and bond β is a single bond; R₄ isH, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃; R₅ is OH, OSi(CH₃)₃,O(C₁-C₄) alkyl, or OCF₃, and bond γ is a single bond, or R₅ is O andbond γ is a double bond; R₆ is H, (C₁-C₄) alkyl, or CF₃; R₇ is H, OH,(C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide, CH₂OCF₃ or OCF₃and bond ε is a single bond, or R₇ is CH₂ and bond ε is a double bond;R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH, orOCF₃; R₁₁ is H, (C₁-C₄)alkyl, halide, OH, or OCF₃ and bond δ is a singlebond; R₁₂ is H, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, p-toluene sulfonyloxy ormethane sulfonyloxy, halide, OH, OCF₃, or R₁₅R₁₆Si, where R₁₅ and R₁₆are each independently (C₁-C₄)alkyl, furanyl or Ph, and bond δ is asingle bond; R₁₁ together with R₁₂ and the carbons to which each isattached to form an oxirane moiety form an ether group and bond δ is asingle bond; or R₁₁ and R₁₂ are absent and bond δ is a double bond; andwherein the composition is free of biological material of illiciumtashiroi.
 19. A composition comprising a compound having the structureof the formula

wherein R₁₃ is C(O)OH, C(O)O(C₁-C₄)alkyl, or C(O)S(C₁-C₄) alkyl.
 20. Acompound having the structure of formula

wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃; R₁₉ is H, O(C₁-C₄)alkyl,(C₁-C₄)alkyl, halide, OCF₃, or CF₃; R₂₀ is H, p-toluene sulfonyloxy,methane sulfonyloxy, C(O)(C₁-C₄) alkyl, or OC(O)(C₁-C₄)alkyl, and bond αis a single bond or R₂₀ is O and bond α is a double bond; R₂₁, R₂₄, andR₂₅ are each independently H, O(C₁-C₄)alkyl, (C₁-C₄) alkyl, halide,OCF₃, or CF₃; R₂₂ is a halide, H, or (C₁-C₄)alkyl; and R₂₃ is H,O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph.
 21. A process ofproducing a compound of the formula

wherein, R₁ is H, Bn, Bz, (C₁-C₄)alkyl, or CF₃; R₂ is H, (C₁-C₄)alkyl,halide, OC(O)(C₁-C₄)alkyl, OC(O)Ph, or OCF₃; R₃ is p-toluenesulfonyloxy, methane sulfonyloxy, C(O)(C₁-C₄)alkyl, orOC(O)(C₁-C₄)alkyl, bond α is a single bond and bond β is a double bond,or R₃ is O, bond α is a double bond and bond β is a single bond; R₄ isH, I, Br, Cl, Si(CH₃)₃, (C₁-C₄)alkyl, or OCF₃; R₅ is OH, OSi(CH₃)₃,O(C₁-C₄)alkyl, or OCF₃, and bond γ is a single bond, or R₅ is O and bondγ is a double bond; R₆ is H, (C₁-C₄)alkyl, or CF₃; R₇ is H, OH,(C₁-C₄)alkyl, CH₂OBn, CH₂O(C₁-C₄)alkyl, CH₂OH, halide, CH₂OCF₃ or OCF₃and bond ε is a single bond, or R₇ is CH₂ and bond ε is a double bond;R₈, R₉, and R₁₀ are each independently H, (C₁-C₄)alkyl, halide, OH, orOCF₃; and R₁₁ and R₁₂ are each independently H, (C₁-C₄)alkyl, halide,OH, or OCF₃ and bond δ is a single bond, R₁₁ together with R₁₂ and thecarbons to which each is attached to form an oxirane moiety form anether group and bond δ is a single bond or R₁₁ and R₁₂ are absent andbond δ is a double bond, comprising subjecting a compound of the formula

wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₀, and R₁₁ are defined as above;and R₁₃ is —C(O)OH, —C(O)O(C₁-C₄)alkyl, or —C(O)S(C₁-C₄)alkyl, to atandem oxidative dearomatization-transannulation Diels-Alder reaction toobtain the compound.
 22. A process of producing a compound of theformula

wherein, R₁₈ is H, (C₁-C₄)alkyl, or CF₃; R₁₉ is H, O(C₁-C₄)alkyl,(C₁-C₄)alkyl, halide, OCF₃, or CF₃; R₂₀ is H, p-toluene sulfonyloxy,methane sulfonyloxy, C(O)(C₁-C₄)alkyl, or OC(O)(C₁-C₄)alkyl, bond α is asingle bond and bond β is a double bond or R₂₀ is O, bond α is a doublebond and bond β is a single bond; R₂₁, R₂₄, and R₂₅ are eachindependently H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, halide, OCF₃, or CF₃; R₂₂is a halide, H, or (C₁-C₄)alkyl; and R₂₃ is H, O(C₁-C₄)alkyl,(C₁-C₄)alkyl, halide, OCF₃, CF₃ or Ph comprising reacting a compound ofthe formula

with a compound of the formula

to obtain the compound.
 23. A process of producing a compound of theformula

comprising a) reacting the compounds of the formulae

wherein R₁ are defined as above, with Pd₂(dba)₃, ^(t)Bu₃P, and DMF toobtain a compound of the formula

b) reacting the product of step a) with DMP and DCM to obtain a compoundof the formula

c) reacting the product of step b) with a compound of the formula

BuLi, and THF to obtain a compound of the formula

d) reacting the product of step c) first with MsCl and TEA and then withMe₂Cu(CN)Li₂ to obtain a compound of the formula

e) reacting the product of step d) with TBAF and THF to obtain acompound of the formula

f) and reacting the product of step e) with PIDA and Toluene to therebyobtain the compound.
 24. A process of producing a compound of theformula

comprising b) reacting a compound of the formula

with NaBH₄ and MeOH to produce a compound of the formula

b) reacting the product of step a) with TMS-Imid to produce a compoundof the formula

c) reacting the product of step b) with mCPBA and DCM to produce acompound of the formula

d) reacting the product of step c) with H₂, Pd/C 5%, and EtOAc toproduce a compound of the formula

e) reacting the product of step d) with an acid in water to therebyobtain the compound.